Central nervous system in cerebral malaria: 'Innocent bystander' or activeparticipant in the induction of immunopathology?

Cerebral malaria (CM) is a major life-threatening complication of Plasmodiu m falciparum infection in humans, responsible for up to 2 million deaths an nually. The mechanisms underlying the fatal cerebral complications are stil l not fully understood. Many theories exist on the aetiology of human CM. T he sequestration hypothesis suggests that adherence of parasitized erythroc ytes to the cerebral vasculature leads to obstruction of the microcirculati on, anoxia or metabolic disturbances affecting brain function, resulting in coma. This mechanism alone seems insufficient to explain all the known fea tures of CM. In this review we focus on another major school of thought, th at CM is the result of an over-vigorous immune response originally evolved for the protection of the host. Evidence in support of this second hypothes is comes from studies in murine malaria models in which T cells, monocytes, adhesion molecules and cytokines, have been implicated in the development of the cerebral complications. Recent studies of human CM also indicate a r ole for the immune system in the neurological complications. However, it is likely that multiple mechanisms are involved in the induction of cerebral complications and both the presence of parasitized erythrocytes in the cent ral nervous system (CNS) and immunopathological processes contribute to the pathogenesis of CM. Most studies examining immunopathological responses in CM have focused on reactions occurring primarily in the systemic circulati on. However, these also do not fully account for the development of cerebra l complications in CM. In this review we summarize results from human and m ouse studies that demonstrate morphological and functional changes in the r esident glial cells of the CNS. The degree of immune activation and degener ation of glial cells was shown to reflect the extent of neurological compli cations in murine cerebral malaria. From these results we highlight the nee d to consider the potentially important contribution within the CNS of glia and their secreted products, such as cytokines, in the development of huma n CM.